The objectives of the proposed program are to carry out clinical pharmacokinetic and biopharmaceutic studies to increase the safety and efficacy of drug therapy in man. A Clinical Pharmacokinetics Laboratory at a major general hospital under the direction of a qualified clinical pharmacokineticist - supported by a panel of specialists in pharmacokinetics, drug analysis, clinical pharmocology, and by an already operative fully-staffed drug information center - will develop individualized dosage regimens for such drugs as digoxin, diphenylhydantoin, quinidine, theophyllin, gentamycin and several other antibiotics based on physiologic and pharmacokinetic parameters, and will explore pharmacokinetic aspects of unusual drug responses and special problems such as drug dosage for patients undergoing hemodialysis. These regimens will be refined and adjusted on the basis of regular monitoring of plasma concentrations and (where feasible) response. Determination of relationships between plasma concentrations and drug action will be carried out in collaboration with a Medical Studies Group of physician-specialists. The effect of the clinical pharmacokinetics program on the quality of therapy will be evaluated with the aid of independent consultants. The clinical research will be interdigitated with a comprehensive program focusing on a) the development of specific and sensitive analytical methods for drugs in plasma, with emphasis on miniaturization (for pediatric use), automation, and determination of free (non-plasma protein bound) drug; b) basic pharmacokinetics research on drug bioavailability, time course of reversible pharmacologic effects, chemotherapy, and development of physiologically realistic biomathematical models; and c) biopharmaceutic research directed to the development of pro-drugs to minimize drug inactivation during absorption, the design of new drug delivery systems for poorly water-soluble drugs, the chemical and physical stabilization of drugs in dosage forms, and the characterization and control of solid state changes (polymorphic transformation, solvates) for the purpose of achieving and assuring better bioavailability.